More on Halting the Lenalidomide Trial

Please read my immediate prior post on this trial first if you have not already to best understand the context of this post.

I heard from a respected investigator and my person physician in my ibrutinib trial, Dr. John Byrd, involved in the halted trial of Revlimid (lenalidomide) versus Leukeran (chlorambucil) in the elderly with CLL. 

He said the Kaplan Meir curves were narrowing. Deaths are now 28 versus 36, but still with more in the lenalidomide arm. He also said "The cause of death was interspersed among many different causes." And he reiterated "We are very excited about lenalidomide as an immune modulating agent at lower doses" suggesting that we might find use for it at a low dose by not only considering its potential to control the CLL, but also to rebuild our damaged immunity. 

This is completely consistent with the additional information presented below from the well balanced reporting of the Myeloma Beacon News.

I have pasted the last half of their article on the topic, the part that is most pertinent to CLL.

Lessons learned?

1. Don't rush to judgement: Analyze all the data and don't generalize.
2. Don't throw out the baby with the bathwater: Immune modulating drugs may be an important piece in solving the CLL puzzle.
3. Expect the unexpected: Be prepared for something that you are are completely unprepared for.

Here is the last half  on the article. The full  article is available at this link but I jumped to the part that is more focused on CLL

As I said in my prior post, this is an evolving story.

Revlimid Leukemia Trial Halted – No Immediate Impact On Drug’s Use In Myeloma Expected

By Julie Shilane

Published: Jul 19, 2013 4:52 pm

The decision to halt the ORIGIN study was based on an analysis conducted in March that showed CLL pa­tients treated with Revlimid had a 92 percent increased risk of dying compared to those treated with chlor­am­bucil.  Specifically, 16 percent of patients treated with Revlimid had died at that point, compared to 9 percent of patients treated with chlorambucil.

Click on image to view a larger version of it.

The results from the March analysis show that a dif­ference between the overall survival curves started to emerge around 6 months after the start of treatment (see graph on the right).

Celgene told The Beacon that the gap in the sur­viv­al curves has since grown smaller, but has not closed, and that the death rates are currently 18 percent for Revlimid and 13 percent for chlor­am­bucil.  These findings, however, have not yet been reviewed or confirmed by the FDA.

The FDA also has not yet released any information about what factors may have increased the risk of death among Revlimid-treated patients.  A spokes­per­son from the agency told The Beacon, “The FDA is working with [Celgene] to gather the infor­ma­tion needed to better understand the nature of the deaths.”

Greg Geissman, a spokesperson from Celgene, provided some additional information to The Beacon.  He explained that secondary cancers have not contributed to the increased risk of death among patients treated with Revlimid in this study.  He added that secondary cancers were balanced between the two treatment groups, both in terms of the rate of patients developing secondary cancers and the number of deaths at­trib­ut­able to secondary cancers.

Geissman also stated, “As we understand, a preliminary observation shows a greater imbalance in deaths in patients over the age of 80 who have co-morbidities [additional medical conditions]. Our analysis will now look to understand further some of these dynamics and how they may have contributed to the imbalance.”

In addition to analyzing the potential impact of age and co-morbidities on the survival imbalance, Celgene stated that the company will analyze differences in how the patients were cared for at the various centers involved in the study.  The company indicated that the results from these analyses will be presented at an upcoming medical meeting.

The Mayo Clinic’s Dr. Kumar also explained that “Other studies of Revlimid in CLL have shown that these patients can have unique side effects compared to myeloma patients, such as tumor flare.”

A tumor flare reaction is a temporary worsening of symptoms soon after treatment begins.  It can be a sign that treatment is working, but it requires that patients be monitored closely during the first few weeks of treat­ment.

“Given that the [survival] curves start separating out close to a year, it is unlikely that [tumor flare] explains the increased mortality, but it clearly would be one of the aspects to be examined in the future,” explained Dr. Kumar.

“As we know more details about the cause of deaths in the Revlimid arm in the CLL study,” added Dr. Kumar, “we should certainly evaluate if there are specific patients with myeloma where there might be a concern.”

Lenalidomide (Revlimid) Associated with Excess Deaths in the Elderly

Honestly, I didn't see this coming. The IMIDs (immuno-modulating drugs such as lenalidomide or Revlimid) are touted as kinder gentler and safer therapy for the elderly.

Not so says this trial. 

What it found instead in an interim analysis was a significant increase in the number of deaths for those taking lenalidomide compared to those on the old school chemo drug, chlorambucil, an oral alkylating agent.

Now of course the details on the causes of the excessive deaths will help unravel this story, but for now it is a cautionary tale as why we need trials to test what seem to be safe and logical assumptions.

Does this mean if you are in another trial with lenalidomide, you should stop? Absolutely not, but you should discuss with your doctor what this means in your particular circumstance. Probably nothing if you are doing well.

Now this is a newsflash, and the full story is far from told, but since it is a popular non-chemo option out there, I wanted to share this ASAP.

Personally, I still believe there is a role for IMIDs in CLL (too many patients have done well with them), but my bigger belief is that we really have a very primitive understanding of how they work.

We have begun to crack the biology on B cell receptors pathways and BCL-2, but what exactly Revlimid is doing is murky. 

And usually our best results come when we have nailed the underlying basic science. Some drugs have come to us in the past from plain dumb luck, but most of the breakthrough today are based on meticulous pre-clinical basic research.

Here's the news:

GEN News Highlights : Jul 18, 2013

Celgene Halts a Phase III B-Cell CLL Trial Because of Deaths

Celgene today said that after a consultation with the FDA it will stop administering Revlimid® (lenalidomide) in its open-label, Phase III ORIGIN® trial because of patient deaths.

“An imbalance was observed in the number of deaths in patients treated with lenalidomide versus patients treated with chlorambucil,” Celgene said.

The trial, which FDA placed on clinical hold July 12, was intended to evaluate the efficacy and safety of lenalidomide versus chlorambucil as single agent in elderly patients 65 and older with B-cell chronic lymphocytic leukemia (CLL), plus comorbidities that precluded treatment with more aggressive standard chemo-immunotherapies.

The firm noted that, in this particular trial, there were 34 deaths out of 210 patients in the lenalidomide arm compared with 18 deaths out of 211 patients in the chlorambucil group. It added that “all other Celgene-sponsored chronic lymphocytic leukemia clinical trials with lenalidomide are continuing in accordance with their respective protocols.”

Revlimid is approved in the US for the treatment of patients with mantle cell lymphoma whose disease has relapsed or progressed after two prior therapies. The drug is also approved in the US, Canada Switzerland, Australia, and New Zealand, Malaysia, Israel, and “several Latin American countries”—according to Celgene—for the treatment of transfusion-dependent anemia due to low- or intermediate-1-risk MDS associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities. In Europe, the drug is also approved for the treatment of similar patients with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate. Revlimid is not approved as a CLL treatment.

ASH 2012: Dr. Tom Kipps Explains why Understanding CLL Biology Helps us Focus Therapies: Bcl-2 and ABT-199; as well as my Reporting on the Suspended Trials

This is the first of a four part interview with my doctor, Dr. Tom Kipps, where he unpacks for us the complexities of why Bcl-2 is such an attractive target in CLL.

This is not a theoretical construct, but is directly pertain to a powerful drug that is in clinical trials right now: ABT-199. That power is a double edged sword and I discuss the recent news about the trial suspensions later in this post.

It turns out that of the all the B-cell cancer, CLL is guilty of the greatest overproduction of this Bcl-2 which is a strong cellular anti-suicide messenger. Twin that with the contravening fact that CLL cells also overproduce the powerful pro-apoptotic (programmed cell death) compound BIM. But BIM is held in check by the excess Bcl-2.  Block Bcl-2 and then the BIM goes bam and the cancer cell suicides.

Vey good.

That is where ABT-199 comes in. But I will let Dr. Kipps explains.



Now all this power to take the safety off the suicide bomber inside every CLL cell comes with a heavy cost. If it is too effective, especially in someone with a high tumor burden (read very high lymphocyte count and huge nodes) and /or there is a significant dose escalation, the cell death toll can exceed the body's ability to cope with all the waste produced by the broken down cells. This is the dreaded tumor lysis syndrome( see this nice explanation by Dr. Sharman), and it can not only kill the patient, it can kill the development of a life saving drug.

Very bad.

I have waited until there was a reliable public source for confirmation before posting this information on my blog and I got it today from Bloomberg news.

I quote:

AbbVie Inc., the drug company that split off from Abbott Laboratories at the start of the year, suspended five studies on its experimental leukemia and lymphoma medicine after two patient deaths.

The patients died from tumor lysis syndrome, said Tracy Sorrentino, a spokeswoman for North Chicago, Illinois-based AbbVie. The complication stems from the rapid destruction of malignant cells after treatment that can trigger acute kidney failure. It occurs most often with large tumors such as those found in leukemia and lymphoma patients, according to the National Institutes of Health. 

They continue:

“We have every expectation that these trials will come off the partial clinical hold and we’ll be able to initiate Phase 3 trials in 2013 as planned,” she said. “ABT-199 is a highly- potent agent and can result in the tumors reducing really quickly,” she said. “We are working to refine the dose.”

After the complication was discovered, AbbVie and its partner, Roche Holding AG, suspended the dose- escalation portion of the studies to determine the amount of drug that is safest and most effective, Sorrentino said. The risk stems from the drug’s potency and can be managed if the dose is carefully controlled, she said. 

This is a very powerful oral medication that has a tremendous potential to help even the worst risk patients with CLL. I want to have this option available in the near future to the many of us who might benefit from it, but not at the cost of moving too fast in the clinical trials. I agree that now that we know the danger, we can take appropriate precautions. 

Personally, if  I wasn't already doing so great on my ibrutinib trial, I would not hesitate to enter an appropriate ABT-199 trial once they have the dose escalation reworked. If anything, they are going to be over cautious from here forward.

Hence my prior post on dotting the I's and crossing the T's that was my loud admonition to take it slow with drug trials.

Nice and easy does it every time.